Growth of the mammalian ovary is regulated by both the endocrine and nervous systems. During the past year of support we have gathered additional evidence in support of the concept that ovarian development is subjected to the regulatory influence of a "neuroendocrinotrophic" complex. This complex consists of three basic components the extrinsic innervation to the gland, an intragonadal source of catecholamines, and growth factors of the neurotrophin family. We have found that neurotransmitters acting via the cyclic AMP generating system contribute to the early differentiation of newly formed ovarian follicles by facilitating formation of FSH receptors, before the ovary becomes responsive to gonadotropins. Using mice carrying null mutations of genes encoding neurotrophins (nerve growth factor [NGF], neurotrophin-4 [NT-4], brain derived neurotrophic factor [BDNF]) or the receptor that mediates the actions of NT-4 and BDNF (trkB), we found that neurotrophins are r equired for the initial development of primordial follicles. The nonhuman primate gland contains an intrinsic network of neuron-like cells, some of which are catecholaminergic. These neurons derive from the neural crest, migrate into the ovary during fetal life, become more abundant as the animal approaches puberty, and all but disappear during aging. In addition to this intrinsic source of catecholamines, monkey oocytes are able to uptake dopamine (DA) via a DA transporter and convert it into norepinephrine (NE). In turn, NE activates ?-adrenoreceptors in adjacent granulosa cells, which respond with cAMP formation. Since cAMP inhibits oocyte maturation, oocyte-derived catecholamines may represent one of the cell-to-cell mechanisms involved in the autoregulation of oocyte maturation. In addition to their role in early follicular development, neurotrophins also participate in the ovulatory process. The expression of trkA, the tyrosine kinase receptor of NGF, increases in the ovary during the preovulatory surge of gonadotropins of both rodents and primates. Purified bovine thecal cells, transfected with a trkA expression vector to simulate a periovulatory condition, respond rapidly to NGF with prostaglandin E2 formation and proliferation. Thus, NGF may contribute to the ovulatory process by facilitating the formation of inflammatory mediators and the differentiation of thecal cells into their luteal counterparts. FUNDING NIH HD-24870. PUBLICATIONS Lara HE, Leyton V, Fiedler JL, Dissen GA, Ojeda SR. An increase in ovarian neurotrophins contributes to the development of polycystic ovary. Soc Neurosci Abstr 24:2005, 1998 (abstract #801.9). Mayerhofer A, Smith GD, Danilchik M, Levine JE, Wolf DP, Dissen GA, Ojeda SR. Oocytes are a source of catecholamines in the primate ovary Evidence for a cell-cell regulatory loop. Proc Natl Acad Sci USA 95:10990-10995, 1998.